Review Article Available Online through ... · Review Article Available Online through DIFFERENT APPROACHES TO DESIGN AND EVALUATION OF COLON SPECIFIC DRUG DELIVERY SYSTEMS Sateesh

Sateesh Kumar Vemula*, Prabhakar Reddy Veerareddy / Int.Journal Of Pharmacy&Technology

IJPT | December 2009 | Vol. 1 | Issue No.1 | 1-35 Page 1

Review Article Available Online through

www.ijptonline.com DIFFERENT APPROACHES TO DESIGN AND EVALUATION OF CO LON

SPECIFIC DRUG DELIVERY SYSTEMS Sateesh Kumar Vemula* and Prabhakar Reddy Veerareddy

St.Peter’s Institute of Pharmaceutical Sciences, Vidyanagar, Hanamkonda. E-Mail: [email protected].

Received On: 11-11-2009 Accepted On: 28-11-2009

ABSTRACT Oral administration of different dosage forms is the most commonly used method due to greater

flexibility in design of dosage form and high patient acceptance, but the gastrointestinal tract presents

several formidable barriers to drug delivery. In oral colon-specific drug delivery system, colon has a

large amount of lymphoma tissue (facilitates direct absorption in to the blood), negligible brush

boarder membrane activity, and much less pancreatic enzymatic activity as compared with the small

intestine. Colon-specific drug delivery has gained increased importance not just for the delivery of the

drugs for treatment of local diseases associated with the colon but also for its potential for the delivery

of proteins and therapeutic peptides. Different approaches are designed based on prodrug formulation,

pH-sensitivity, time-dependency (lag time), microbial degradation and osmotic pressure etc to

formulate the different dosage forms like tablets, capsules, multiparticulates, microspheres, liposomes

for colon targeting. The efficiency of drug delivery system is evaluated using different in vitro and in

vivo release studies. This review updated the research on different approaches for formulation and

evaluation of colon-specific drug delivery systems (CDDS).

Keywords: Colon specific drug delivery system, Microbial degradation, Osmotic

Pressure, pH-sensitivity, Prodrug, Time dependency.



INTRODUCTION

In the past two decades, the pharmaceutical scientists are extensively investigated in the area of

colonic region for targeted drug delivery system. Targeted drug delivery to the colon is mainly for the

treatment of colonic diseases, for drugs like proteins and peptides, for the treatment of diseases

sensitive to circadian rhythms such as Asthma, Angina and Rheumatoid arthritis and for delivery of

steroids, which absorbable in colon. The advent of slow release technologies increase the chances for a

drug to be released in the colon and thus this organ has an important role to play in drug absorption

from oral sustained release formulations.

In 1942, Svartz discovered that sulfasalazine; the sulfanilamide prodrug of 5-

aminosalicylicacid (5-ASA) is effective in the treatment of rheumatoid arthritis and anti-inflammatory

disease. The exact mode by which the drug target itself to the colon was elucidated much latter in 1970

i.e., colon specific azoreductase splits sulfasalazine causing the release of the active moiety 5-

aminosalicylicacid. After the several other azo-bonds containing compounds designed to locally

release 5-aminosalicylicacid were synthesized bensalazine, balsalazide and olsalazine. In1986, Saffron

and coworkers described the use of azo containing acrylic polymers to the delivery of protein drugs

like insulin to the colon (Girish et al. 2006).

Colon-specific drug delivery system offers the following therapeutic advantages (Girish et al. 2006,

Chourasia et al. 2003, Sarasija et al. 2000, Vyas and Roop, 2006):

• Reducing the adverse effects in the treatment of colonic diseases (ulcerative colitis, colorectal

cancer, crohn’s disease etc.)

• By producing the ‘friendlier’ environment for peptides and proteins when compared to upper

gastrointestinal tract.

• Minimizing extensive first pass metabolism of steroids.



• Preventing the gastric irritation produced by oral administration of NSAIDS.

• Delayed release of drugs to treat angina, asthma and rheumatoid arthritis.

To achieve successful colon targeting it should overcome the following limitations (Jack et al., 2006).

• The location at the distal portion of the alimentary canal, the colon is difficult to access.

• Successful delivery requires the drug to be in solution before it arrives in the colon, but the fluid

content in the colon is lower and more viscous than in upper GIT, which is the limiting factor for

poorly soluble drugs.

• Lower surface area and relative tightness of the tight junctions in the colon can restrict drug

transport across the mucosa in to the systemic circulation.

ANATOMY AND PHYSIOLOGY OF COLON

Irrespective of therapy desired for local (colonic) or systemic delivery of drug, the development and

aim of the drug delivery to colon remains same (Vyas and Roop, 2006), that is

• The drug must not absorb from other regions of the gastro intestinal tract (GIT).

• It should only suffer negligible degradation in the small intestine lumen.

• The release of the drug in the colon should be at quantitatively controlled rate and the released

drug in the colon should be absorbed from the lumen of the large intestine without any appreciable

degradation.

In order to meet these properties, a thorough knowledge of the anatomy and physiology of GIT is

required. In GIT, large intestine starts from the ileocecal junction to the anus with a length of about 1.5

meters (adults) and is divided into three parts; they are colon, rectum and anal canal. The colon is the

upper five feet of large intestine and mainly situated in the abdomen. The colon is a cylindrical tube

lined by mucosa. The cecum, colon ascends, colon transversale, colon descendens and recto sigmoid

colon made of the colon. Colon is made up of four-layers, serosa, muscularis externa, sub mucosa, and



mucosa. The colon does not have villi, but due to presence of plicae semilunares (cresentic folds) the

intestinal surface of the colon is increased to approximately 1300 cm2. CDDS is primarily dependent

on the following physiological factors; they are the pH level, the transit time and the microbial

environment in the colon, which are governing the release rate of drug from different designs of

CDDS (Vyas and Roop, 2006, Vincent et al.2002). Different properties of GIT were given in (Table 1)

and different enzymes present in colon, which are responsible for microbial degradation, were reported

by Vincent et al (2002).

Table 1: Properties of Gastro Intestinal Tract

Region of GIT Property Measured value

Total GIT

Small intestine -Duodenum -Jejunum -Ileum

Large intestine -Cecum -Ascending colon -Descending colon -Transverse colon -Sigmoid colon -Rectum -Anal canal

Small intestine Large intestine

Stomach Duodenum Jejunum Ileum Colon Rectum

Colon -Right -Mid -Left

Surface area

Length

Length

Internal diameter

PH

Redox potential

2-106 cm2

20-30 cm 150-250 cm 200-350 cm

6-7 cm 20 cm 45 cm 30 cm 40 cm 12 cm 3 cm

3-4 cm 6 cm

1 3.5 5-7 6-7 7 5.5-7 7

- 415 - 400 - 380



COLONIC ABSORPTION OF DRUGS

The surface area of the colon is much less compared to small intestine and is compensated by absence

of endogenous digestive enzymes and long residence time of colon (10-24 hours). Different factors

affecting colonic absorption were reported by Vincent et al (2002).

• Passes through colonocytes (Trans cellular transport).

• Passes between adjacent colonocytes (Para cellular transport).

Transcellular absorption involves the passage of drugs through cells and thus the route for most

lipophillic drugs takes, where as paracellular absorption involves the transport of drug through the

tight junctions between the cells and is the route of most hydrophilic drugs (Vyas and Roop, 2006).

Drugs shown to be well absorbed include glibenclamide, diclofencac, theophylline, ibuprofen,

metoprolol and oxyprenolol. Drugs shown to be less absorbed include furosemide, pyretanide,

buflomedil, atenolol, cimetidine, hydroclorthiazide, lithium and ciprofloxicin (Sarasija et al. 2000).

Different types of absorption enhancers used in CDDS reported by Vincent et al (2002).

DRUGS SUITABLE FOR CDDS

Based on literature review, the following different categories of drugs are suitable for colon drug

delivery.

• Drugs used to treat irritable bowel disease (IBD) require local delivery at drug to colon e.g.

sulfasalazine, olsalazine, mesalazine, steroids like fludrocortisone, budesonide, prednisolone and

dexamethasone.

• Drugs to treat colonic cancer require local delivery e.g. 5-fluorouracil, doxorubicin, and

methotrexate.

• Protein and peptide drugs - eliminating drug degradation e.g. growth hormones, calcitonin, insulin,

interleukin, interferon and erythropoietin.



• To treat infectious diseases (amoebiasis & helminthiasis) - requires site specific delivery e.g.

metronidazole, mebendazole and albendazole,

• To treat rheumatoid arthritis (NSAIDS), nocturnal asthma, angina require delay in absorption due

to circadian rhythms

• Drugs showing more selective absorption in colon than small intestine due to small extent of

paracellular transport e.g. glibenclamide, diclofencac, theophylline, ibuprofen, metoprolol, and

oxyprenolol.

DIFFERENT APPROACHES

Prodrug Approach

A prodrug is pharmacologically inactive derivative of a parent drug molecule that requires

spontaneous enzymatic transformation in vivo to release the active drug (Sinha and Rachana, 2001a).

In this method the prodrugs (Table 2) are designed to undergo minimum absorption and hydrolysis in

the upper GIT and undergo enzymatic hydrolysis in the colon, there by releasing the active drug

moiety from the carrier.

Different types of conjugates were used to prepare 5-ASA prodrugs, which are succeed in

releasing the 5-ASA in colonic region. They are biodegradable poly (ether-ester) azo polymers

(Samyn et al.1995), azo-linked polymeric prodrugs (Etienne et al.1996), acrylic type polymeric

prodrugs (Soodabeh et al.1997) and cyclodextrin prodrugs (Kaneto et al.1997). Glucuronide prodrugs

were developed for corticosteriod to deliver the drug to the large intestine of colitic rats (Harold et

al.1997). Azo-containing urethane analogues synthesized for colon drug delivery. A urethane-based

analogue containing an azo aromatic linkage in the backbone was synthesized by reacting touline-2, 6-

diisocyanate with a mixture of an aromatic azodiol (Chavan et al. 2001).



Cyclodextrin prodrugs were prepared by conjugating 5-ASA on to the hydroxyl groups of α-,

β-, γ-cyclodextris through an ester linkage and investigated the release in cecum and colon. After oral

administration in rats the conjugate passed through stomach and small intestine without degradation or

absorption and in the cecum and/or colon site-specific degradation of conjugate released 5-ASA (Mei

et al. 2005). An azo prodrug of 5-ASA with histidine was synthesized for targated drug delivery to the

inflammated gut tissue in inflammatory bowel disease. The synthesized prodrug was found to be

equally effective in mitigating the colitis in rats, as that of sulfasalazine without the ulcerogenicity of

5-ASA and adverse effective of sulfasalazine (Nagpal et al. 2006).

In a recent study by Yunjin et al. (2006), explained the potential of 5- amino salicyliltaurine as

a colon specific prodrug of 5ASA by in vivo evaluation to treat experimental colitis. The prodrug was

prepared by conjugating 5ASA with taurine and tested in 2,4,6, trinitrobenzene sulfonicacid (TNBS)

induced colitis rats. Taurine conjugation of 5-ASA greatly reduced absorption of 5-ASA from the

intestine. Oral administration of the conjugate not only increased the colonic delivery efficiency of 5-

ASA but also decreased the systemic absorption of free 5-ASA as compared to other conjugates

prepared with glycine and asparticacid. Taurine conjugate of 5-ASA is slightly more effective than

sulfasalazine in alleviating the colonic inflammatory induced by TNBS. N-Nicotinoylglycyl-2-(5-

fluorouracil-1-yl)-D, L-glycine was synthesized as a prodrug of 5-fluorouracil colon specific drug

delivery (Lee et al. 2007).

PH-Dependent System

The basic principle in this method is the coating of the tablets/pellets etc with various pH

sensitive polymers (given in Table 2), which will produce delayed release and also give protection

from gastric fluids. Selection of polymers is important thing. The selected polymers to colon targeting

should be able to withstand the pH of the stomach and small intestine. Methacrylic acid esters most



commonly used polymers for colon targeting because they are soluble at above pH 6. The ideal

polymer should be able to withstand the lower pH of the stomach and of the proximal part of the small

intestine but able to disintegrate at neutral or shortly alkaline pH of the terminal ileum and preferably

at ileocecal junction. Eudragit L and Eudragit S are widely used in the colon targeting because

Eudragit L is soluble at pH 6 or above and Eudragit S is soluble at pH 7 or above and the combination

of these polymers give the desirable release rates.

A novel colon-specific drug delivery system was developed with methacrylate derivatives of 5-

ASA using pH sensitive swelling and drug release properties (Davaran et al. 2001). Composite film

coated tablets of 5-ASA were prepared for colon specific delivery. In this method 5-ASA core tablets

were prepared and coated with dispersion contained Eudragit RS and dessterrifed pectin,

polygalacturonic acid, or its potassium and sodium salts. Negligible drug release occurred during first

five hours where the coated tablets were in the stomach and small intestine. After that the release of 5-

ASA from coated tablets occurred linearly as a function of time due to the action of pectinolytic

enzymes (Sriamornsak et al. 2003).

A comparison study of the usual enteric-coated polymers viz. Eudragit, Cellulose acetate

phthalate with Shellac and Ethyl cellulose as carriers for colon specific drug delivery was conducted to

select a suitable carrier. In this study lactose based indomethacin tablets were prepared and coated

with one of the above coating polymers to a varying coating thickness. From the dissolution data at a

coat concentration of 3% shellac provided the most appropriate polymer coat for colon-specific drug

delivery. Variation in the shellac coat thickness can facilitate drug delivery to terminal ileum, distal or

proximal colon (Sinha et al. 2003).

EUDRACOLTM is a novel pH and time controlled multiple unit colon drug delivery systems in

which the pellets coated with Eudragit RL /RS and Eudragit FS 30D. Caffeine is used as marker drug



for pharmacokinetic studies using the multi particle principle and delayed release in the colon;

reduction of dosing frequency may be achieved. Due to its specific coating structure, the Eudracol

system offers a new dimension for colon drug targeting via the oral route (Brigitte et al 2003). 5-ASA

pellets were coated with the enteric coating solution containing different ratios at Eudragit L-100 and

Eudragit S-100 for colon drug delivery. The release of 5-ASA is depending on the thickness of the

layer and the ratio of Eudragit copolymers (Gang et al. 2004). PH-sensitive hydrogels were prepared

for colonic delivery of therapeutic peptides, proteins. New pH-sensitive glycopolymers were

developed by free radical polymerization of methacrylic acid and 6-hexandiol diacrylate and 6-

hexandiol propoxylate diacrylate (Mahkam M, 2007).

Time-Dependent System

The basic principle involved in the system is the release of drug from dosage form should be

after a predetermined lag time to deliver the drug at the right site of action at right time and in the right

amount (Shweta, et al., 2006). Colon targeting could be achieved by incorporating a lag time into

formulation equivalent to the mouth to colon transit time. A nominal lag time of five hours is usually

considered sufficient to achieve colon targeting. In this method the solid dosage form coated with

different sets of polymers (listed in Table 2) and the thickness of the outer layer determines the time

required disperse in aqueous environment.

Colon drug delivery system of diclofencac sodium (DS) was developed using time dependent

approach. In this, diclofencac sodium tables were coated with ethylcelluese in ethanol solution cooling

diethyl phthalate as a plasticizer and PEG 400 as channeling agent. The lag time of DS release was

primarily controlled by thickness of ethycellulose coating layer. By increasing the thickness of the

coating layer, longer the lag time of DS release (Gang et al. 2004).



Formulation of fast release enteric coated tablets for colon drug delivery using two different

approaches .The first one is using super disintegrate and the second one is based on osmogen. In the

first approach core tablets (celicoxib as a model drug) were prepared using different concentrations of

super disintegrates like cross-linked PVP. In second approach concentrations tablets were prepared

using potassium chloride, sodium chloride as osmogen. Then they are coated with Eudragit L-100:

Eudragit S-100 in the ratio of 1:5 to achieve a desired thickness. The tablets with super disintegrates

are fast released where the tablets with osmogen are sustain released. The coat weight determines the

lag phase that required eliminating the release in stomach and small intestine (Sinha et al. 2006).

Hydroxy Propyl Methyl Cellulose (HPMC) compression coated tablets of 5-fluorouracil were

studied for colon drug delivery that based on time-dependent approach. In this, the core tablet was

prepared by wet granulation method and then coated with 50% of HPMC/lactose coat powder by

compression-coating method. Drug release characteristics were evaluated in distilled water by using a

Chinese pharmacopoeia rotatable basket method (Wu B et al. 2007).

Micro flora Activated System

The basic principle involved in this method is degradation of polymers coated on the drug

delivery system by microflora present in colon and there by release of drug load in colonic region

because the bioenvironment inside the human GIT is characterized by presence of complex microflora,

especially the colon is rich in microorganisms (Sinha, Rachana, 2003). In this method drugs and/or

dosage forms are coated with the biodegradable polymers (Table 2) i.e., the polymers degrade due to

influence of colonic microorganisms. When the dosage form passes through the GIT, it remain intact

in the stomach and small intestine where very little microbial degradable activity is present which is

insufficient for cleavage of the polymer coating.



Table-2: Materials used in Formulation of CDDS

5-ASA pellets were coated with amylose for colon drug delivery, in which amylose coating

solution was prepared along with Ethocel, Eudragit RS/RL 30D and Aquacoat ECD 30 (Snezana et al.

1996). Chitosan capsules were developed for colon specific delivery of insulin and its absorption was

improved by addition of absorption enhancers (sodium glycocholate, sodium oleate) and protease

Prodrug conjugates PH-Sensitive Polymers

Materials used In Time-Dependent System

Microbial degradable polymers

Azo bond conjugates Amino acid (Polypeptide) conjugates Glycoside conjugates Glucuronide conjugates and Sulphate conjugates Polymeric conjugates Cyclodextrin conjugates Dextran conjugates

Eudragit L-100 Eudragit S-100 Eudragit L-30 D Eudragit L-100-55 Eudragit F S 30 D Poly Vinyl Acetate Phthalate Hydroxy Propyl Methyl Cellulose Phthalate 50 Hydroxy Propyl Methyl Cellulose Phthalate 55 Hydroxy Propyl Ethyl Cellulose Phthalate Cellulose Acetate Phthalate Cellulose Acetate Trimellate

Hydroxy Propyl Methyl Cellulose Hydroxy Ethyl Cellulose Ethyl Cellulose Microcrystalline Cellulose Hydroxy Propyl Methyl Cellulose Acetate Succinate Lactose/Behinic acid

Chitosan Pectins Guar gum Dextrans Inulin Lactulose Amylose Cyclodextrins Alginates Locust bean gum Chondroitin sulphate Boswellia gum



inhibitors like bacitracin, aprotinin (Hideyuki et al. 1997). Low swelling guar gum prepared by corss-

linking with glutaraldehyde that is used as a colon-specific drug carrier (Irit et al. 1998). Chitosan

succinate and chitosan phthalate were synthesized by reacting the chitosan separately with succinic

anhydride and phthalic anhydride. These semisynthetic polymers produced stable matrices of

diclofencac sodium for colon specific delivery that had more resistance to acidic condition and

improved drug release profile under basic conditions (Khaled et al. 1999).

Organic acids like succinicacid, tartaricacid and citricacid were used as excipients in matrix

granules to modify the drug release for colon-specific drug delivery (Nykanen et al. 1999). Amylose-

Ethylcelluese film coatings obtained from organic-based solvents were investigated as potential

vehicles for colon drug delivery. In this method amyulose-butanol dispersion and ethycellulose in

ethyllacttate/ethnol/propanol with dibutylsebacate as plasticizer were mixed in various proportions and

coated on 5-ASA pellets to achieve desired thickness. The drug release regulating parameters are

thickness of coating and ratio of amylose to ethylcelluese. The release of drug is irrespective of the

solvent used for coating. Formulation containing 1 part amylase and 1 part ethylcelluose of coating

thickness, 15% TWG, gives desired release profiles of 5-ASA for colon targeting (Lee et al. 2000).

Phosphated cross-linked guar gum was prepared for colon-specific drug delivery. Guar gum

cross-linked with increasing amounts of trisodiumtrimetaphosphate to reduce its swelling properties

for use as a vehicle in oral delivery formulations, especially drugs aimed at localizing in the distal

portions of the small bowel. Swelling of guar gum in artificial GI fluids was reduced from 100-120-

fold to 10-35-fold depending on the amount of cross linker used (Irit et al. 2000).

Colon target drug delivery system for mebendazole was developed using guar gum as a carrier.

In this method mebendazole matrix tablets containing various proportions of guar gum were prepared

by wet granulation technique using starch paste as a binder. From the results 20% and 30% guar gum



tablets were provided targeting of mebendazole for local action in the colon (Krishnaiah et al. 2001).

The α-cyclodextrin derivate of prednisolone-21-succinate showed anti-inflammatory activity with low

adverse effects when compared to prednisolone alone by intra colonical administration to rats with

2,4,6, trinitrobenzene sulfonicacid-induced colitis. The conjugate can alleviate the systemic adverse

effect of prednisolone while maintaining the therapeutic activity of prednisolone (Hideki et al. 2001).

A chitosan-dispersed system (CDS) was developed for colon- specific drug delivery, in which

the capsule containing acetaminophen was coated with the suspension containing chitosan powder and

Eudragit RS, formed a drug release-regulating layer around the capsule. Outer enteric coating layer

prevent the dissolving of chitosan under acidic pH. The resultant enteric-coated CDS capsules reached

the large intestine with in one to three hours after oral administration and they were degraded at the

colon in beagle dogs (Norihito et al. 2002). Masataka et al. (2002), Libo et al. (2003) were studied

about the lactulose as a carrier for colon-specific drug delivery by microbial degradation in colon.

Enteric-coated pectin based matrix tablets were prepared for colonic delivery of theophylline.

This approach takes advantage of the combination of pH-sensitive method and microbial-triggered

system. In this method theophylline-colon biodegradable pectin matrix tablets were prepared and

coated with enteric coating solution (Eudragit S100 in acetone) to overcome the poor compactability

of pectin. Emdex, a hydrophilic directly compressible material was used to prepare tablets by direct

compression (Paola et al. 2003). The new quaternized chitosan i.e. triethyl chitosan (TEC) is evaluated

in pharmaceutical approaches and proved that there is a significant increase in absorption of poorly

absorbed compounds in colon specific drug delivery system (Parisa et al. 2004).

Calcium pectinate beads were prepared for colon specific delivery of therapeutic peptides like

bovine serum albumin (BSA) by extruding BSA-loaded pectin solution to an agitating calcium

chloride solution and gelled spheres were formed instantaneously by an ionotropic gelation reaction.



The drug release was regulated by concentration of pectin, concentration of calcium chloride

and total drug loading (Atyabi et al. 2005). The HPMA Copolymer (N-(2-hydroxy propyl)

methacrylamide)-9 amino camptothein conjugate containing a spacer was synthesized and

characterized for oral colon specific drug delivery. The drug delivery system has potential in the

treatment of colon cancer (Song-Qi et al. 2006 and Shinji et al. 2001). Zinc pectinate beads formed the

strongest network matrix in comparison with calcium pectinate and suggested the zinc pectinate beads

as efficient carriers for specific drug delivery to colon (Chambin et al. 2006).

Metronidazole tablets were prepared using various polysaccharides like guar gum, xanthan

gum, pectin, carrageenan, β-cyclodextrin for colon specific drug delivery to treat ameobiasis

(Mundargi et al. 2007). 5-Fluorouracil compression coated tablets were prepared for colonic release of

drug using xanthan gum, boswellia gum and HPMC as the coating materials (Sinha et al. 2007).

CDDS of 5-fluorouracil was developed using pectin-ethyl cellulose as a film coat with Fluidized bed

coater (Wei et al. 2007).

Combination of Different Approaches of CDDS

An oral colonic drug delivery system of 5-ASA was developed using combination of pH-

dependent, time-based and enzyme degradable approaches. The pellets were coated with three

functional layers i.e. the outer EudragitL30D-55 layer for protection against GI fluids, the intermediate

layer of ethyl cellulose to inhibit the drug release during passage through the small intestine and the

inner layer of pectin for swelling and enzyme-degradation. In vitro release studies indicated that the

coated pellets completely protected the drug release in 0.1M HCl while the drug release was delayed

for three to four hours in pH 6.8 phosphate buffer (Fude et al. 2007).



Pulsatile device was formulated to achieve time- or site-specific release of theophylline based on

chronopharmaceutical consideration. The basic design consists of an insoluble hard gelation capsule

body filled with Eudragit microcapsules of theophylline and sealed with a hydrogel plug and finally

the enteric device was enteric coated. In this approach, pH sensitive and time dependent delivery

systems were combined. In this the thickness of enteric coat is a measure of protection from stomach

and intestine pH. Different hydrogel polymers were used as plugs to maintain a suitable lag period.

The hydrophilic polymer content is a measure of delayed release of theophylline from microcapsules

(Mastrholimath et al. 2007).

Pectin based CDDS of 5-fluorouracil was developed using calcium pectinate gel. Calcium

pectinate gel beads were prepared by ionotropic gelation method followed by enteric coating with

Eudragit S-100 and evaluated using USP paddle type dissolution apparatus in different simulated

mediums (Jain et al. 2007).

A new microbial-triggered colon targated osmotic pump (MTCT-OP) was developed for

CDDS based on chitosan for a model drug, budesonide. The combination of osmotic technology and

microbial-triggered mechanism had a high potential to deliver to drug load in colonic region. In this

method the core tablet of budesonide was prepared with chitosan, which is used to produce osmotic

pressure, and to form the insitu delivery pores for colon-specific drug release. Cellulose acetate in

acetone along with chitosan (as pore forming agent) was coated on tablet as a semipermiable

membrane and finally coated with Eudragit L-100-55 in ethanol as an enteric coating layer that could

prevent cellulose acetate membrane from forming pore or rupture before reaching colon region.

Budesonide release from developed system was inversely proportional to the osmotic pressure to the

release medium (Liu et al 2007).



Hydrogel based CDDS

Amydated pectin hydrogel beads prepared for colon specific delivery of indomethacin and

sulfamethoxazole (Munjere et al 1997). Glutaraldehyde cross-linked dextran capsules were prepared

for colon targeting. Along with magnesium chloride and PEG 400 in water the capsule caps and bodies

were prepared on nylon molding pins. Then the dextran capsules were filled with model drug

(Hydrocortisone) and drug release was studied. The drug release pattern was suitable for colon specific

delivery (Bronsted et al. 1998). The hydrogels formed by cross-linked polyvinyl alcohol were suitable

for colon specific drug delivery systems. In this method polyvinyl alcohol of different molecular

weights was corss-linked with succinyl, adipoyl, or sebacoyl chloride to obtain hydrogel-forming

polymers. The hydrophilic drugs like diclofencac sodium, propranolol hydrochloride and vitamin B6

hydrochloride were used as model drugs (Orient et al. 2001). Methacrylated inulin hydrogels designed

for colon targeting the proteins like Bovine serum albumin or Lysozyme (Vanden et al. 2003). Organic

redox-initiated polymerization technique was used to fabricate pH responsive hydrogels for colon

specific delivery (Emmanuel et al. 2003).

Glutaraldehyde corss-linked guar gum hydrogel discs were prepared as vehicles for colon

specific drug delivery of ibuprofen. Percent drug release increased with glutaraldehyde concentration.

Cross-linking decreased the swelling of guar gum. The fabricated hydrogels discs may prove to be

beneficial as colon-specific drug delivery vehicles for poorly water-soluble drugs like ibuprofen (Adit

et al. 2006).

Novel complex hydrogel beads were prepared using pectin and zein for colon-specific drug

delivery. Pectin/Zein complex hydrogel beads showed the capability to protect incorporated drugs

from premature release into stomach and small intestine. The inclusion of a small portion of zein (a

protein from corn) in to the pectin efficiently suppressed the swelling behavior of pectin, thus



stabilizing the structural property of the pectin networks. Like wise the pectin networks protected the

bound zein from protease digestion. These properties made pectin/zein complex beads a promising

system for colon specific drug delivery (Linshu et al. 2006). Cross-linked HPMC hydrogels were

synthesized and used to develop 5-ASA colon drug delivery system (Davaran et al. 2007).

NOVEL DRUG DELIVERY SYSTEMS FOR CDDS

Now a days the basic CDDS approaches are applied to formulate novel drug delivery systems

like Multiparticulate systems, Microspheres, Liposomes, Microencapsulated particles etc.

Multiparticulate systems

Multiparticulates (pellets, non-peariles etc.) are used as drug carriers in pH-sensitive, time-

dependent and microbially control systems for colon targeting. Multiparticulate systems have several

advantages in comparison to the conventional single unit for controlled release technology, such

asmore predictable gastric emptying and fewer localized adverse effect than those of single unit tablets

or capsules (Laila and Sanjeev, 2006).

A multiparticulate dosage from was prepared to deliver active molecules to colonic region,

which combines pH dependent and controlled drug release properties. This system was constituted by

drug loaded cellulose acetate butyrate (CAB). Microspheres loaded by an enteric polymer (Eudragit

S). Here the enteric coating layer prevents the drug release below pH 7. After that CAB microspheres

efficiently controlled the release of budesonide, which is depended on the polymer concentration in the

preparation (Marta, Jose et al. 1998). Azo polymer coated pellets were used for colon-specific drug

delivery to enhance the absorption of insulin and (Asu1,7) Eel calcitonin (Hideyuki et al. 2001). A

multiparticulate chitosan dispersed system (CDS) was prepared for colon drug delivery and it was

composed of the drug reservoir and the drug release-regulating layer, which was composed of water

insoluble polymer and chitosan powder. The drug reservoir was prepared by drug containing



multiparticulates like Non peariles in the study. In this study the multiparticulate CDS was adopted not

only for colon specific drug delivery but also for sustained drug delivery (Norihito et al. 2003).

A multiparticulate system combining pH sensitive property and specific biodegradability was

prepared for colon targated delivery of metronidazole. The multiparticulate system was prepared by

coating cross-linked chitosan microspheres explorting Eudragit L-100 and S-100 as pH sensitive

polymers. The in-vitro drug release studies shows that no release of drug at acidic pH and higher drug

release was found in presence of rat caecal contents indicating susceptibility of chitosan matrix to

colonic enzymes released from rat caecal contents (Chourasia and Jain 2004). High-Amylose

cornstarch and Pectin blend microparticles of diclofencac sodium for colon-targeted delivery were

prepared by spray drying technique. The blending of high-amylose cornstarch with pectin improved

the encapsulation efficiency and decreased the drug dissolution in the gastric condition from pectin-

based microparticles. The drug released in colonic region by the action of pectinase from

microparticles (Kashappa, 2005).

Masataka et al. (2006) investigated the effect of sodium glycocholate as an absorption

promoter on orally administrated insulin absorption utilizing a colon-targeted delivery system. A novel

insulin colon-targeted delivery system (Insulin- CODES) contains insulin, lactulose as a trigger for

colon-specific release, citricacid as a solubilizer of insulin, meglumine as a pH adjusting agent and

sodium glycocholate as an absorption promoter.

Microspheres of anti-cancer drugs

Cross-linked guar gum microspheres containing methotrexate were prepared and characterized

for local release of drug in the colon for efficient treatment of colorectal cancer. In this method

glutaraldehyde was used as a cross-linking agent and guar gum microspheres were prepared by

emulsification method. From the results of in vitro and in vivo studies the methotrexate loaded cross-



linked guar gum microspheres delivered most of the drug load (79%) to the colon, where as plain drug

suspensions could deliver only 23% of there total dose to the target tissue (Mohini et al. 2006).

Colon specific microspheres of 5-fluorouracil were prepared and evaluated for the treatment of

colon cancer. In this method core microspheres of alginate were prepared by modified emulsification

method in liquid paraffin and by cross-linking with calcium chloride. The core microspheres were

coated with Eudragit S-100 by the solvent evaporation technique to prevent drug release in the

stomach and small intestine. The results showed that this method had great potential in delivery of 5-

fluorouracil to the colon region (Ziyaus et al. 2006).

Other novel drug delivery systems

A new microparticulate system containing budesonide was prepared by microencopsulition for

colon specific delivery (Marta et al 2001).

In the study by Liu et al. (2003) a novel formulation for bee venom peptide was developed

using coated calcium alginate gel beads-entrapped liposome and investigated for colon specific drug

delivery in vitro. The release rate of bee venom from formulation was dependent on the

concentration of calcium and sodium alginates and the amount of bee venom in the liposome, as well

as coating. A human γ-scintigraphy technique was used for in vivo studies and the results showed that

this formulation had great potential for colon-specific drug delivery. A novel colon specific drug

delivery system containing flubiprofen microsponges was designed. Microsponges containing

flubiprofen and Eudragit RS100 were prepared by quasi-emulsion solvent diffusion method and/or

flubiprofen was entrapped in to a commercial microsponge-5640 system using entrapment method.

Using these flubiprofen microsponges the colon specific tablets were prepared using triggering

mechanism. The particulate form (microsponges) has been used to provide more uniform distribution



of the drug in the colon and help the drug to spread on the colon surface in an appropriate way (Mine

et al. 2006).

EVALUATION OF CDDS

The drug release in the colonic region from different CDDS is evaluated by different methods

of in vitro and in vivo release studies, which show the success rate of different designs of colon drug

delivery systems. Depending upon the method of preparation different evaluation methods are

proposed. A successful colon specific drug delivery system is one of that remains intact in the

physiological environment of stomach and small intestine, but releases the drug in the colon.

In-vitro Evaluation

Different in vitro methods are used to evaluate the colonic drug delivery systems. In in-vitro

studies the ability of the coats/carriers to remain intact in the physiological environment of the

stomach & small intestine is assessed by drug release studies in 0.1N HCl for two hours (mean gastric

emptying time) and in pH 7.4 phosphate buffer for three hours (mean small intestine transit time)

using USP dissolution apparatus. In case of micro flora activated system dosage form, the release rate

of drug is tested in vitro by incubating in a buffer medium in the presence of either enzymes (e.g..

pectinase, dextranase) or rat/guinea pig / rabbit caecal contents. The amount of drug released at

different time intervals during the incubation is estimated to find out the degradation of the carrier

under study (Libio et al, 2002).

In-vivo Evaluation

Like other controlled release delivery systems, the successful development of the CDDS is

ultimately determined by its ability to achieve release in colonic region thus exerts the intended

therapeutic effect. When the system design is concerned & prototype formulation with acceptable in

vitro characteristics is obtained, in vivo studies are usually conducted to evaluate the site specificity of



drug release and to obtain relevant pharmacokinetic information of the delivery system. Although

animal models have obvious advantages in assessing colon specific drug delivery systems, human

subjects are increasingly utilized for evaluation of this type of delivery systems. The preferable

animals to evaluate CDDS are rats, guinea pigs and dogs (Libio et al, 2002).

γ-scintgraphic studies were conducted in human volunteers with technetium-99m-DTPA as

tracers in sodium chloride core tablets compression coated with guar gum showed that the gum coat

protect the drug (tracer) from being released in the stomach and small intestine. On entering the

ascending colon, the tablets commenced to release the tracer indicating the breakdown of gum coat by

the enzymatic action of colonic bacteria (Krishnaiah et al. 1998a). Technetium-99m-DTPA was used

as a tracer for γ- scintigraphy evaluation of colon specific guar gum directly compressed matrix tablets

in human volunteers (Krishnaiah et al. 1998b). The scintgraphic evaluation conducted for capsule type

colon specific drug delivery system in human healthy volunteers (Ishibashi et al. 1998). In a study by

Krishnaiah et al. (2001), showed the effect of metronidazole and tinidazole (antimicrobial agents) on

the release of albendazole from guar gum based colon specific matrix tablets. The active antimicrobial

agents (7 days) treatment of rat caecal content decreased the release of albendazole due to decreased

levels of anaerobic bacteria present in rat. Sangalli et al. (2001) studied the evaluation of

chronotopicTM oral system to achieve time and/or site-specific release. In this study in vitro drug

release studies were carried out in a USP 24 paddle apparatus. The in vivo testing, performed on

healthy volunteers, envisaged the HPLC determination of antipyrine salivary concentration and a γ-

scintgraphic investigation to point out the break-up of the units occurred in the colon.

The suitability of different tracers like Tc-DTPA (technisium-99m-diethylene triamine penta-

aceticacid) and Tc-sulphur colloid studied for γ- scintigraphy evaluation of CDDS in healthy human

volunteers and concluded that DTPA is a suitable targeting for 99m-Tc for evaluation of CDDS



containing water soluble drugs by γ- scintigraphy (Krishnaiah et al. 2002). The suitability of locust

bean gum and chitosan for bacterially triggered colon specific drug delivery system was studied by in

vitro and in vivo drug release studies (Chellan et al. 2002). In vitro evaluation studies were carried out

for colon specific tablets containing different binders like xanthan gum, guar gum, chitosan and

Eudragit E. From the results formulation with chitosan and Eudragit E would be highly site specific

(Sinha et al. 2002). In a study by Jinhe et al. (2002) proved that apparatus III (reciprocating cylinder

method) was more convenient and efficient than apparatus-II (paddle type) by producing various

programmable options in sampling times, agitation rates and medium changes and suggested that

apparatus-III approach has better potential for in vitro evaluation of CDDS. Summery of general

dissolution on conditions for paddle (USP APP-II) and reciprocating cylinder methods (USP APP-III)

was reported by Jinhe et al. (2002).

In vitro evaluation studies were conducted for chitosan-containing microparticulate system for

colon drug delivery. In this study fluorescin isothiocyanate-labelled bovine serum albumin (FITC-

BSA) was used as a model drug. The chitosan hydrogel beads which containing trypolyphosphte as

counter ion. The protein release experiments were carried out in vitro under different conditions to

simulate the pH and times likely to be encountered drug intestinal transit to the colon. Release of

FITC-BSA form the chitosan beads was studied in sealed 25ml conical flasks in a Magniwhirl*

constant temperature shaker bath at 370C and 60 SPM. Enzymatic degradations of chitosan by

pancreatin and by porcine pancreatic lipase present in simulated intestinal fluid were studied using a

viscometric procedure (Hua et al. 2002). The pharmacokinetic evaluation of guar gum based colon-

targeted tablets of mebendazole against an immediate release tablet was carried out in human

volunteers. Six healthy volunteers participated in the study and a crossover design was followed. In

this study, on oral administration of colon-targeted tablets mebendazole started appearance in the



plasma at five hours and reached the peak plasma concentration at 9.4 ± 1.7 hrs (Tmax) where as the

immediate release tablets produced at 3.4 ± 0.9 hrs (Tmax) the results of the study indicated that the

guar gum based colon targeted tablets of mebendazole did not release the drug in stomach and small

intestine, but delivered the drug to the colon resulting in a slow absorption of the drug and making the

drug available for local action in colon (Krishnaiah et al. 2003).

The colon-specific matrix tablets of mesalazine with guar gum were evaluated invtro and in

vivo studies. In vitro dissolution studies using a flow-through cell apparatus with and without

galactomannase enzyme. In-vivo studies conducted in healthy humans using X-ray imaging technique

to monitor the tablets throughout the GI system in which barium sulphate as a marker (Fatmanual et al.

2004). Tablets consisting of flubiprofen microsponges were developed for colon specific delivery and

dissolution test was conducted in USP rotating paddle apparatus at 37±0.50C and 50 RPM. Initial drug

release studies were done in 750 ml of 0.1 N HCl for two hours. Then 250 ml of 0.2 M trisodium

phosphate solution was added to the dissolution media and the pH was adjusted to 6.8 with 2N HCl for

eight hours. Samples were withdrawn after regulated time intervals and analyzed

spectrophotometrically at 248 nm. For the study of enzymatic degradation same method was used, but

at eighth hour pectinexultra SP-L was added to the dissolution media to simulate the enzymatic action

to the colonic bacteria (Mine et al. 2006).

CONCLUSION

From past two decades, considerable amount of research work has been carried out in the area

of colon targeting. By considering the advantages of CDDS like providing friendlier environment for

protein and peptide drugs that reducing the adverse effects in the treatment of colonic diseases, site-

specific release to treat colonic cancer, amoebiasis, and helminthiasis etc, minimizing the extensive

first pass metabolism of steroids and produces delay in absorption of drugs to treat rheumatoid



arthritis, angina and nocturnal asthma etc., different approaches are designed to develop colonic drug

delivery system. The release of drug load in colon region is depended on pH of GIT, gastro intestinal

transit time and microbial flora and their enzymes to degrade coated polymers and breaking bonds

between carrier molecule and drug molecule. The preferred CDDS is that should release maximum

drug load in colon region. Among different approaches the pH dependent system is less suitable than

others due to the large inter and intra subject variation in the gastro intestinal pH, but gives better

results with combination of time-dependent system, microbially activated system and others. Different

polymers are used to prepare CDDS by various approaches and are evaluated for their efficiency and

safety.

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Current Author Address:

Sateesh Kumar Vemula*

St.Peter’s Institute of Pharmaceutical Sciences.

Warangal Dist.

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Review Article Available Online through ... · Review Article Available Online through DIFFERENT APPROACHES TO DESIGN AND EVALUATION OF COLON SPECIFIC DRUG DELIVERY SYSTEMS Sateesh